Novel ATR Inhibitor in Breast Cancer: Phase I Data Suggest Phase II Trial Warranted
Posted: Friday, October 29, 2021
Patients with advanced breast cancer with specific molecular alterations may benefit from the highly selective ATR inhibitor RP-3500, according to phase I trial results. Timothy A. Yap, PhD, of The University of Texas MD Anderson Cancer Center, and colleagues presented initial data highlighting the agent’s safety and preliminary efficacy during the 2021 American Association for Cancer Research–National Cancer Institute–European Organisation for Research and Treatment of Cancer (AACR-NCI-EORTC) Virtual International Conference on Molecular Targets and Cancer Therapeutics (Abstract P054).
This first-in-human trial is reportedly the most extensive biomarker-selected study to test an ATR inhibitor as a single agent in cancers harboring synthetic lethal genomic alterations in DNA damage repair pathways. A total of 17 biomarkers in breast cancer, including BRCA1/2, as well as in other solid tumors, were potentially targetable by RP-3500, according to the team.
The early efficacy was seen in resistant and refractory diseases, including BRCA1- and BRCA2-mutated breast cancer that had previously been treated with PARP inhibitors. In addition, Yap and co-investigators reported that the agent induced “meaningful clinical benefit across a variety of gene alterations in 34 of 69 evaluable patients…including 8 with early significant decreases in tumor markers and tumor shrinkage.”
The most common treatment-emergent adverse events were grade 1 or 2 anemia, fatigue, and decreased appetite, and grade 3 anemia occurred in about 22% of treated patients. Therefore, the researchers determined the recommended phase II dose and schedule, other primary endpoints along with safety and tolerability, to be 160 mg once daily for 3 days, followed by 4 days off.
The other solid tumor types and genetic alterations in which RP-3500 showed promise, according to the researchers, included ATM- or CDK12-mutated castration-resistant prostate cancer, PARP inhibitor–resistant ovarian cancer with BRCA1 or RAD51C mutations, BRCA1-mutated head and neck squamous cell carcinomas, and BRCA2-mutated melanoma.
Disclosure: The study authors’ disclosure information can be found at AACR.org.
AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics
